1z8a: Difference between revisions
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[[Image:1z8a.gif|left|200px]] | [[Image:1z8a.gif|left|200px]] | ||
'''Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor''' | {{Structure | ||
|PDB= 1z8a |SIZE=350|CAPTION= <scene name='initialview01'>1z8a</scene>, resolution 0.95Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene> and <scene name='pdbligand=62P:6-[(5-CHLORO-3-METHYL-1-BENZOFURAN-2-YL)SULFONYL]PYRIDAZIN-3(2H)-ONE'>62P</scene> | |||
|ACTIVITY= [http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] | |||
|GENE= | |||
}} | |||
'''Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1Z8A is a [ | 1Z8A is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Z8A OCA]. | ||
==Reference== | ==Reference== | ||
High-resolution crystal structure of aldose reductase complexed with the novel sulfonyl-pyridazinone inhibitor exhibiting an alternative active site anchoring group., Steuber H, Zentgraf M, Podjarny A, Heine A, Klebe G, J Mol Biol. 2006 Feb 10;356(1):45-56. Epub 2005 Nov 10. PMID:[http:// | High-resolution crystal structure of aldose reductase complexed with the novel sulfonyl-pyridazinone inhibitor exhibiting an alternative active site anchoring group., Steuber H, Zentgraf M, Podjarny A, Heine A, Klebe G, J Mol Biol. 2006 Feb 10;356(1):45-56. Epub 2005 Nov 10. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16337231 16337231] | ||
[[Category: Aldehyde reductase]] | [[Category: Aldehyde reductase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
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[[Category: tim-barrel]] | [[Category: tim-barrel]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 15:32:26 2008'' | ||
Revision as of 16:32, 20 March 2008
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| , resolution 0.95Å | |||||||
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| Ligands: | and | ||||||
| Activity: | Aldehyde reductase, with EC number 1.1.1.21 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor
OverviewOverview
The crystal structure of a novel sulfonyl-pyridazinone inhibitor in complex with aldose reductase, the first enzyme of the polyol pathway, has been determined to 1.43 angstroms and 0.95 angstroms resolution. The ternary complex of inhibitor, cofactor and enzyme has been obtained by soaking of preformed crystals. Supposedly due to low solubility in the crystallisation buffer, in both structures the inhibitor shows reduced occupancy of 74% and 46% population, respectively. The pyridazinone head group of the inhibitor occupies the catalytic site, whereas the chloro-benzofuran moiety penetrates into the opened specificity pocket. The high-resolution structure provides some evidence that the pyridazinone group binds in a negatively charged deprotonated state, whereas the neighbouring His110 residue most likely adopts a neutral uncharged status. Since the latter structure is populated by the ligand to only 46%, a second conformation of the C-terminal ligand-binding region can be detected. This conformation corresponds to the closed state of the specificity pocket when no or only small ligands are bound to aldose reductase. The two conformational states are in good agreement with frames observed along a molecular dynamics trajectory describing the transition from closed to open situation. Accordingly, both geometries, superimposed in the averaged crystal structure, correspond to snapshots of the ligand-bound and the unbound state. Isothermal titration calorimetry has been applied to determine the binding constants of the investigated pyridazinone in comparison to the hydantoin sorbinil and the carboxylate-type inhibitors IDD 594 and tolrestat. The pyridazinone exhibits a binding affinity similar to those of tolrestat and sorbinil, and shows slightly reduced affinity compared to IDD 594. These studies elucidating the binding mode and providing information about protonation states of protein side-chains involved in binding of this novel class of inhibitors establish the platform for further structure-based drug design.
About this StructureAbout this Structure
1Z8A is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
High-resolution crystal structure of aldose reductase complexed with the novel sulfonyl-pyridazinone inhibitor exhibiting an alternative active site anchoring group., Steuber H, Zentgraf M, Podjarny A, Heine A, Klebe G, J Mol Biol. 2006 Feb 10;356(1):45-56. Epub 2005 Nov 10. PMID:16337231
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